Oncotarget

Research Papers:

Selective Inhibitors of Nuclear Export (SINE) compounds block proliferation and migration of triple negative breast cancer cells by restoring expression of ARRDC3

Young Hwa Soung, Trinayan Kashyap, Thalia Nguyen, Garima Yadav, Hua Chang, Yosef Landesman and Jun Chung _

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Oncotarget. 2017; 8:52935-52947. https://doi.org/10.18632/oncotarget.17987

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Abstract

Young Hwa Soung1, Trinayan Kashyap2, Thalia Nguyen3, Garima Yadav1, Hua Chang2, Yosef Landesman2 and Jun Chung1

1Department of Pathology, Stony Brook Medicine, Stony Brook, NY 11794, USA

2Karyopharm Therapeutics, Inc. Newton, MA 02459, USA

3University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA

Correspondence to:

Jun Chung, email: Jun.Chung@stonybrookmedicine.edu

Keywords: arrestin related domain containing 3 (ARRDC3), Selective Inhibitors of Nuclear Export (SINE) compounds, selinexor, exportin-1 (XPO-1), triple negative breast cancer (TNBC)

Received: January 20, 2017     Accepted: May 06, 2017     Published: May 18, 2017

ABSTRACT

Arrestin-related domain-containing protein-3 (ARRDC3) is one of 6 mammalian arrestins, which suppresses metastasis by inducing degradation of phosphorylated β2-adrenergic receptor (β2 AR) and integrin β4 (ITG β4). Our previous studies demonstrated that expression of ARRDC3 is epigentically silenced in Triple Negative Breast Cancer (TNBC) cells, and the forced expression of ARRDC3 significantly reduced the invasive potential of TNBC cells. In the current study, we found that Selective Inhibitors of Nuclear Export (SINE) compounds (KPT-185 and selinexor (KPT-330)) restore ARRDC3 expression in TNBC cell lines (MDA-MB-231 and MDA-MB-468) at both the mRNA and protein level in a dose and time course dependent manner. SINE compounds inhibit the proliferation, pro-invasive migration and anchorage independent growth of the TNBC cells by restoring ARRDC3 expression. We found that ARRDC3 expression is lower in TNBC cell lines than those of luminal breast cancer cell lines, and inversely correlated with IC50s of selinexor. Analysis of tissue microarray confirmed that ARRDC3 expression in patient samples is significantly lower in the majority of TNBC tumors relative to normal tissue. In vivo, selinexor inhibited the tumor growth of MDA-MB-231 xenografts by nearly 100% compared with vehicle treated animals. Furthermore, immunohistochemical analysis of TNBC tumors from selinexor treated mice revealed increased ARRDC3 expression versus vehicle treated animals. Our results suggest that restoration of ARRDC3 expression is an important antineoplastic mechanism of SINE compounds in TNBC, and therefore selinexor could be an effective treatment option for breast tumors with down-regulated ARRDC3.


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